ZOE Science & Nutrition - 'Miracle' weight loss drug Ozempic is approved. But does it work?

Episode Date: March 30, 2023

A miracle weight loss drug that’s approved in the US and the UK and has few side effects? Ozempic is going viral on social media. Users are posting dramatic before and after pictures of their weight loss. An Ozempic trend is allegedly blossoming in Hollywood, and famous personalities like Elon Musk claim to have taken it.  Many remain doubtful, dismissing the craze as just another internet scam preying on people’s insecurities. However, earlier this month - semaglutide - the drug’s active ingredient, was approved as a weight loss treatment by the UK’s National Health Service. Even the most sceptical are taking note. Jonathan speaks to Dr Robert Kushner the lead investigator of the huge phase 3 clinical trial that evaluated the safety and effectiveness of semaglutide. He is a founder of the American Board of Obesity Medicine and hailed the drug as a ‘game-changer’ in regards to the treatment of obesity. Please be aware: Dr. Kushner is also a consultant on the medical advisory board for Novo Nordisk - the company that manufactures semaglutide. Dr Robert Kushner is a Professor of Medicine at Northwestern University and a founder of the American Board of Obesity Medicine.  Download our FREE guide — Top 10 Tips to Live Healthier: https://zoe.com/freeguide Timecodes: 03:17 – Quickfire questions 04:20 – What is Ozempic, and how does it work? 05:54 – Treating obesity like diabetes 10:24 – The ‘gamechanger’ Semiglutide clinical trial 14:19 – The role our ancestors play in our weight 17:16 – Short-term weight loss vs long-term weight loss 18:40 – Myths about obesity 21:53 – Obesity, a modern problem 23:56 – Other outcomes of the clinical trial 26:59 – The side effects of Semiglutide 31:45 – Risks of using Semiglutide without medical supervision 33:05 – Is Semaglutide linked to cancer? 36:59 – Can you take it If you’re not obese? 39:15 – The long term commitment of Semiglutide 42:49 – Will I put on weight if I stop taking it? 46:01 – Is this the end of obesity 49:30 – Summary 52:28 – Outro   Episode transcripts are available here. Dr. Robert Kushner’s book, Six Factors to Fit: Weight Loss that Works for You!, is available to buy here Follow Dr. Robert Kushner here  Studies mentioned: Once-Weekly Semaglutide in Adults with Overweight or Obesity  Follow ZOE on Instagram: https://www.instagram.com/zoe/  Want to create your own podcast? Contact Fascinate Productions to bring it to life.

Welcome to ZOE Science and Nutrition, where world-leading scientists explain how their research can improve your health. A miracle weight loss drug that's approved in the US and the UK and has few side effects? Really? A Zempic, a drug originally intended to treat type 2 diabetes, is going viral on social media. Users are posting dramatic before and after pictures of their weight loss. Famous personalities such as Elon Musk claim to have taken it. And an ozempic craze is allegedly developing in Hollywood.

But many are doubtful. Dismissing the craze is just another internet scam preying on people's insecurities. But earlier this month, semaglutide, the drug's active ingredient, was approved as a weight loss treatment in the UK's National Health Service. Now, even the most sceptical are taking note. Could this really be a magic bullet for weight loss? Is it safe? Surely there are side effects. And do you really put all the weight back on if you stop.

In today's episode, we went straight to the source. Dr. Robert Kushner was the lead investigator of the huge phase three clinical trial that evaluated the safety and effectiveness of semaglutide. He is better placed than anyone to explain if this drug really is the miracle cure that we've all been waiting for. Bob is a professor of medicine at Northwestern University and a founder of the American Board of Obesity Medicine. Also joining me today is Zoe's US Medical Director, Dr. Will Bulsiewicz. Bob, thank you for joining us today. Jonathan, it's a pleasure and thank you for having me. Not at all. I can safely say that we had more questions on this topic than any single one that we've run before.

So I'm really excited to do it. It's fascinating. And what I like to do is start, as we always do, with a quick fire round of questions from our listeners. And these are always extremely difficult for professors because we have a simple rule, which is you can say yes, no, or you can give a one sentence answer if necessary, but not more than that. Bob, are you willing to give it a go?

Let's go. Fantastic. Are a Zempik and Wegovy a massive breakthrough for weight loss? Yes. All right. We're already off to a good start. Do drugs like a Zempik and Wegovy mean the end of obesity? No. Can most people lose weight sustainably with calorie counting and willpower? Very challenging. That's why we are now starting to think of using medications.

And finally, if these weight loss drugs will keep me thin, can I stop worrying about what I eat? No. All right. Well, I think that's a brilliant way of sort of setting up the conversation. And what I'd like to do is just start right at the beginning. So there are like these three different drug names that we've started to hear all over the place on the media and social media, which I'm probably pronouncing wrong. So a Zempik, Wegovy, Semaglutide. What are they and how do they work? So Semaglutide or Semaglutide, both are acceptable on how to pronounce the name of the drug. All right.

Thank you, Bob. It mimics a naturally occurring hormone in our body that helps to regulate appetite. So when this naturally occurring hormone is released into the bloodstream after you eat, it helps you start feeling full. It helps you be content between meals. It helps to reduce appetite or hunger. So what the pharmaceutical industry has done is to harness this hormone, reproduce it synthetically into a drug, which is called semaglutide, and give it back to an individual to enhance reduction in appetite. Jonathan is very similar to taking someone with diabetes who has a difficulty making enough insulin and then give them back enough insulin so they can handle their blood sugar. So it's very similar to taking

something that's within our body, giving it back to someone in a pharmacologic sense and improving their condition or the problem that they have. I find it very interesting how effective these drugs are, these GLP-1 agonist drugs. And you just made a comparison to diabetes. And there's two types of diabetes. There's type 1 diabetes, where the person is not able to produce insulin. And then there's type 2 diabetes, where the person has insulin resistance. So they need a higher level of insulin in order to achieve the effect. If this is a similar sort of process in the body, is this GLP-1 more like type 1 where there's a deficiency in obesity, or is this more like type 2 where the body is resistant to GLP-1, so we need higher levels to achieve the same effect? Well, I'm not sure we know exactly. And that gets back to the

whole idea that the condition of excess body weight is not probably one uniform problem like obesity. It's probably obesities. In other words, there are multiple types. You made the comparison of type 1 diabetes and type 2 diabetes. In obesity, there's probably multiple types of excess body fat. There are likely those, and this has been studied, where the GLP-1 level is lower than you would predict after a meal, for example. You get the surge of this releasing hormone, and it's lower in individuals with obesity, but probably not all. There are others where that hormone may not be penetrating deeply enough into the brain where the appetite centers are. So you give higher doses to penetrate into those centers. Some of this is speculative at this point, but we do know that when you give GLP-1 hormone back to

individuals who are struggling with their weight, never feel full, hungry all the time, either there's an insufficient release within their own body or they just need a higher level, not necessarily resistance, but a higher level in order to achieve that effect. Interesting. Okay. So just to play it back real quick, there may be some people out there that they're a little bit GLP-1 deficient and therefore we're fulfilling this for them with the drug, but there may be some others that they just need a higher level. Absolutely correct. We're not sophisticated enough to know who's who. We call them phenotypes, like different presentations of a particular condition. We don't know enough about that. That's cutting edge information. One day,

if we can have an individual who comes to their healthcare professional's office and we can start categorizing these individuals or segmenting them into different types, like we do with diabetes, we will be able to treat them in a more targeted manner. We're not there yet, but that's the direction this whole field is going. At this point, we can give this kind of medication like semaglutide, and we can't really see differences. Some people are more super responsive than others. Some are less responsive. We don't really understand why that is at this point. And Bob, a lot of people will have heard these names, Azempic and Wegovi. How does that fit

into what you've been describing with semaglutide? The drug semaglutide is actually in both of those drugs. The difference is a trade name and what they're approved for. So Ozembic is semaglutide that's approved for individuals with type 2 diabetes. Will was just talking about that at a lower dose. Wagovi is also semaglutide, but this is approved for individuals with obesity and it's approved at a higher dose. So it actually leads to, I think, confusion in the marketplace, but they're actually the exact same drugs under two different trade names and approved for two different medical conditions. You know, this is like when I go to the supermarket and you're saying like, there are different brand names for bleach or the peanut butter or whatever it is. And in this

particular case, you've got two brand names actually have the same active ingredient in, but with different amounts. Is that what you're saying, Bob? They're not licensed for exactly the same thing, but they actually have the same sort of active ingredient, hence some of the confusion? Correct. Let me throw a more wrinkle in this whole story. You could take semaglutide orally, meaning by your mouth, and that's called rhabelsis. That's also approved for diabetes. So you actually have three different forms, two of them used for self-injection shots, a third one orally, and they all contain semaglutide. So just to confuse the listeners enough, that's what the current state is. And Rob, you ran like a huge clinical trial on semaglutide, or you were the lead author on this,

and that was published in the New England Journal of Medicine fairly recently, which for listeners who aren't familiar with it, is one of the absolute top clinical journals, extremely hard to get into. Can you tell us a little about how that trial was run and the results that you saw? And of course, any disclosures that you want to share about it as well? I'm going to actually throw in the very first rapid fire question you asked me is, is it a game changer? And I quickly

said yes, and you were taken back perhaps by that. But that's the trial that you're referring to. Game changer was something the media picked up on when it went globally as a game changing drug. First of all, the trial was called STEP. It was a global trial of about 2,000 individuals in the STEP1 trial, in which individuals, all of them who were overweight or had obesity, many with a medical problem, were randomized blindly to either this new drug or a placebo, which is just an inactive comparator. Individuals were then studied out to over a year and all of them received lifestyle treatment as a foundation. So it wasn't just drug, it was medication or placebo and everyone got lifestyle counseling. And Rob, that means like guidance about what, when you say lifestyle

treatment? Correct. So they all saw either a registered dietitian or a healthcare professional who's trained in nutrition and received guidance on diet. They were asked to track their diet, increase their physical activity, and be aware of their surroundings, social surroundings, and so forth. From a dietary perspective, just to be clear, I believe it was with a calorie deficit of about 500 kilocalories per day. Is that right? That is correct. Everyone got the exact same treatment. So it wasn't tailored or targeted. Everyone got the same lifestyle management. Right. So the group that received the drug and also the group that did not receive the drug, they were all recommended the same diet, the same lifestyle practice.

Correct. And after 68 weeks, when the trial came to an end, what we found is what I thought was game-changing, remarkable, and that is individuals who took a placebo, in other words, just received lifestyle counseling, lost about 3% of their body weight after about a year. Those on the medication, on average, lost 15% of their body weight. In fact, one in three lost 20 or more percent of their body weight. We hadn't seen that before. So in part, that is where that game-changing moniker came from. We've never seen that before. The other reason I've responded yes to Game Changer is that that trial heralded in a new direction for the treatment of obesity, and that is harnessing our intestinal hormones, which we talked about a little bit early.

It's a GLP-1 hormone. That's what's called what semaglutide mimics. It's a GLP-1 hormone, that's what it's called, what semaglutide mimics, is now showing the way for a new treatment direction for the treatment of obesity in which we are now trying to treat obesity hormonally. Again, like diabetes, I keep using that comparison. I'd like to share something exciting. Back in March 2022, we started this podcast to uncover how the latest research can help us live longer and healthier lives. We've spoken to leading scientists around the world doing amazing research. And across hundreds of hours of conversations, they've revealed key insights that can help you to improve your health. If you don't have hundreds of hours to spare,

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and do let me know what you think of it. Okay, back to the show. And you know what's interesting about this all, Bob, you're an endocrinologist so that means that you specialize in hormones, is that it starts to paint a picture that obesity may be a hormonally mediated disease. Can you perhaps talk for a moment about why it's so hard for people to lose weight by reducing calories long-term or by exercising? How does the body adapt when we reduce calories or we start to exercise more? Well, to answer your question, we have to go back millennia. We have to go back with how the body is engineered. We've got time, Bob.

We can just extend the podcast. I'm going to shorten the hundreds of thousands of years, but where I'm going with this, Jonathan, is that we are engineered to maintain our body in times of famine and starvation. So if you go back 100,000 years ago, where normally you would have times of famine, the body developed adaptive ways to survive when there wasn't enough food around. So we're very, very good at hibernating, if you will, and surviving without a lot of food. So our bodies adapt, it shuts down, you don't burn as many calories in order to get through those times where there isn't enough food. So fast forward hundreds of thousands of years.

We don't have famine anymore, but our body is biologically engineered that way. So, Will, if you go on a diet and you try to lose weight, and you can do that pretty successfully early on by reducing your calories, as you said earlier, a calorie deficit. So you start losing weight because you go into an energy imbalance. However, from a biological point of view, our body thinks that it is famine time or starvation time. So it goes into this down adaptation to get you through this period of time. The body is biologically engineered and wired to conspire against you. It does not want to have you lose weight. So it will defend what you weighed before you went on a diet.

Interestingly, even though you had an excess body fat or an excess body weight, the body thinks that's where you ought to be. So as you lose weight from time zero all the way down, the body fights you, biologically that is. And the way you feel it is you start getting hungrier as you try to keep your body weight down. So food feels and looks more enticing. You're not as content eating the same amount of food you did before. So it drives you to eat more. And it actually is even more difficult than that.

Your energy expenditure or your resting metabolic rate, the amount of calories you burn start to go down. So you don't need as many calories as you did when you started. And we also now have identified that your muscles become more efficient. So as you're on a treadmill and you're 3.5 for 30 minutes, you actually don't burn as many calories because your muscles get more efficient in what you're doing. These are all the factors and mechanisms the body puts into place to try to maintain where you were before and prevent you

or make it harder for you to lose more weight. And at some point, individuals start to eat more and they change their diet to what it was. And over time, weight starts to go back up again. So long-winded answer that it's very, very difficult to take weight off and keep the weight off because of the way we are biologically wired. This explains why many people can be successful with a 30-day binge diet and then they bounce back and they have that rebound weight gain because the hormones are changing and you become more hungry, your metabolism slows down, and eventually it reaches a point where your body bounces back to that baseline. Right. Now, there's different stories here.

Now, if you think about an actor in Hollywood who gains 30 pounds for a role in a movie, they're often able to get their weight back down again. It's a short-lived weight gain. Weight comes back down. Individual woman who becomes pregnant will gain excess weight for the baby. Her weight is able to come back down. Individual woman who becomes pregnant will gain excess weight for the baby. Her weight is able to come back down. You go on a holiday, you gain some weight, bring it back down. So you certainly can gain weight and bring it back down. What we think is happening in individuals who suffer from what we call clinical obesity or ongoing long-term obesity is that it's over a longer period of time. It may be in part from the food supply.

There may be inflammation that's going on in the brain. Maybe genetically that you are predisposed to gaining weight over a long period of time. So we don't exactly know the difference between individuals, but for individuals who we call suffer from clinical obesity, that is affecting the quality of life, medical complications, their medical problems associated with weight, those individuals who really have a struggle taking their weight off and keeping it off. And Bob, I think there'll be many people listening to this who are saying, well, it's really interesting because I've just sort of had this slow, steady increase in my weight. You know, I think back to what I was when I was 21 or whatever.

And in many cases, just sort of slowly, steadily going up. And it's always seemed really hard to get back down. And what you're saying is this is a very unfair system, right? There's a sort of easy movement up. And then there's this incredible biological systems that are fighting back. And that therefore, I think a lot of what, you know, certainly I was brought up to believe about weight loss, which is, well, you know, you just reduce your calories. It's just willpower. It's easy. There are basically no scientists that I meet now who still seem to believe in this. Is that fair? It is fair. And I'm so glad you brought that up because it really highlights the continuing societal myths or misunderstanding about what excess body weight or obesity is.

Many people still think it's willpower, it's lack of discipline. Why can't you just stop eating? There's something wrong with your personality, your compulsivity leads you to overweight. We now know so much more that we really do consider obesity, at least in this situation, as a disease. And I think it's very similar to how we used to think about depression or alcoholism or opiate misuse several decades ago. We used to blame people for their alcohol use or they're depressed.

And we would no longer think of telling someone who's depressed, just think happy thoughts and just snap out of it. Why are you so blue? We wouldn't think that way anymore. We used to probably 50 years ago before we understood that depression was a disease with signaling problems and biological basis. We don't think of opiate misuse like that anymore. Individuals on heroin or cocaine, we know they need rehabilitation,

they need help, they need to see a healthcare professional. The same applies to individuals struggling with their weight. We have to get away from this whole stigma and bias that there's something wrong with them and just they need to be motivated and think of it as an underlying biologically and genetically based disease in many individuals and treat them as such. And that then opens the door to thinking about drug use like semaglutide. And Bob, on this show, we end up talking a lot about gut health. We talk a lot about microbiome. We end up talking about foods, particularly the difference between, for example, ultra-processed foods and the sort of foods we used to historically eat a lot. And I'm sort of intrigued that you're describing this drug as sort of a mimic of a

hormone that's actually, you know, comes from our gut, as I understand it. Do we understand whether in fact, there is any interplay here, whether because there has been this extraordinary explosion of obesity, which I think you rightly describe as a disease. And you see the statistics in every country, right? Like when I was little, people used to talk about that very much in America. And what's striking now is you see the same statistics in somewhere like France that used to claim that this wouldn't happen here. So there's a solution coming in that sort of mimics this existing thing created by our body. Do we understand anything

about somehow why this might be more needed today than it was 50 years ago? You are right. The prevalence of obesity has risen dramatically. I just looked at this the other day. In the United States, the prevalence of obesity in 1993 was 13%. It's now 42%. And a projection, at least in the United States, is that it will reach... It's amazing. So from 13% to 42%. Correct. And a projection by 2030, if you use modeling, is about 50% in the United States, defined by body mass index over 30. And Jonathan, as you're alluding to, this is a global problem. Obesity is the single most common non-communicable disease. So COVID, as you're alluding to, this is a global problem. Obesity is the single most common non-communicable disease. So COVID, of course, would be communable, right? You pass along

non-communicable like a chronic illness. Obesity is number one. Change in food supplies, socialization, urbanization, engineering out physical activity, and so forth are presumed reasons. You asked before whether semaglutide would cure obesity or bring an end to obesity, and I said immediately no. Obesity is a chronic relapsing condition or disease that is now spread globally. Obesity is also a public health problem. The game-changing aspect of semaglutide is from a clinical point of view. It's an individual comes to see their healthcare professional. They're suffering from obesity with its complications. Medication makes sense. We're not going to unleash a medication for a public health problem. So you have to have all the stakeholders involved between regulation, food supply, leisure group, built environment, right? Transportation, air pollution, all these things

are factors that may affect obesity. So it's a public health problem and it's a clinical problem. And we have to use the right tool and solutions for both of these. So Bob, you mentioned earlier your New England Journal of Medicine paper, the STEP1 trial. And in that study, the people who did just exclusively the diet and lifestyle, they lost about 3% of their body weight. Talk to us, if you use these drugs, what did you find in your study? What can a person expect in terms of outcomes? So the primary outcome was weight loss, and that's what we talked about earlier, Will. As I tell my colleagues and my patients,

my center, which is Center for Lifestyle Medicine, is not 1-800-THIN. That's not what we're trying to do. We're not trying to make people thin. We're trying to help them be healthier, and weight is one of the metrics of health. So the other metrics of health that were seen in the STEP trial is reduction in blood sugar, although none of them had diabetes in that trial, but those with prediabetes, it improved. Reduction in triglycerides, total cholesterol, LDL cholesterol, reduction in blood pressure, an improvement in CRP, which is inflammatory marker, and very important, the improvement in quality

of life, particularly physical functioning. So those were the outcome measures in the STEP trial. So at the end of the trial, individuals not only lost weight, they were healthier by all of the parameters we were able to measure. Now, that also comes at a balance of what are the side effects of the drug, which we didn't talk about, but it's probably worth mentioning now, is that these medications, all the GLP-1 receptor agonists, that's what they're called, these gut hormone mimics, all the side effects are gastrointestinal. Although it was found to

be safe and effective, individuals were at risk of having at least temporary short-lived side effects, and they're all gastrointestinal, such as nausea, diarrhea, constipation. Some even had vomiting, and some had increased heartburn. In all of the trials, the individuals have these side effects early and they tend to subside as time goes on. There's also an increased risk of gallstones, or we call it gallbladder disease. You have to be aware of that. So it has to be prescribed by a knowledgeable healthcare provider who's going to monitor you. And I would not be recommending this drug just to lose weight or be thin. You know, one of the things that I find interesting as a gastroenterologist is that these are GI side effects.

Nausea is the number one side effect associated with the drug. And there's a very clear explanation for this, which is that when you start taking this drug, it slows down the emptying of your stomach. And we know that in other disease states or conditions, when a person's stomach emptying slows, they can feel nauseated and it's because you get full very quickly. So it's not a big surprise, but this is part of the reason why when a person initiates the drug, they start at a very low dose, a fraction of the ultimate dose they're going to land on, and then they gently work their way up. And if they run into these side effects along the way, they can slow down that dose escalation before they ultimately get to that higher dose that allows them to achieve their goal. Hi, I love that you're listening to this.

It means a lot to me and the whole team who put such a lot of hours into this podcast each week. We release this show for free without ads to help millions of people improve their health with cutting edge science. In return, all I ask is that you help us on this mission. If you know someone who'd benefit from listening to this episode, please send them a link to this show. And if you haven't already, hit follow wherever you're listening right now. Thank you and on with the show. Absolutely correct. And that's a very important point, Will,

that all of them across the board start low, build up slowly, and we've identified we're able to mitigate or reduce those side effects by doing it. There's also another important message regarding how to better tolerate these drugs, and this gets into the diet-nutrition interface, is that if you must consume or you should consume a lower-fat diet, because that also slows gastric emptying, don't overeat.

So when you start feeling full, moderate the amount of food you're eating, and don't skip meals. So those are three things that help to reduce the side effects. In addition, it's starting at a low dose. So we've learned all this through the trials. And now this now has spilled over into clinical care. That's how we counsel individuals. And Bob, I would guess a lot of people listen to this and are saying, those side effects don't sound that bad at all. You're saying I can lose 15% of my body weight.

You know, I might have a bit of nausea, might have a bit of diarrhea. It's probably going to fall away. I mean, I think most people listening are going to say, well, those sound like quite good balances. I was expecting it to be much worse in terms of the side effects. Is that what you're also experiencing as you're now, I guess, both in the trial, in terms of people sticking with it and then after the trial as you and your colleagues are also giving this to patients? We learned a lot about side effects in the trials. And now, of course, we're learning about it in clinical practice. One of the most important things that we tell patients or some of your listeners who may be starting on this drug

is to have realistic expectations when you use this drug. And that is you are likely to have some side effects early on. Pay very careful attention to your diet. I tell patients it's not a race to continue to escalate the dose, which is done, by the way, the medication is given once a week and then we escalate every month. So you take four doses at one dose and then you increase to the higher dose. You give four shots and so forth. I tell individuals, if you are not tolerating as well as you would like, you don't have

to race to get to the next dose. You could actually stay there. The other thing we've noticed, interesting, is that there are some super responders. There are some individuals who don't have to get to a very high dose. They have the benefit of appetite suppression. In fact, some people are so responsive, they will tell me, I don't get hungry anymore. I don't even feel I have to eat. That's too much for them.

So we have to titrate the dose lower for those individuals. But just to make sure I've got that right, because I think a lot of the way I've heard about it, it's sort of like this, okay, it's an injection, but it's like a magic pill. And we're used to sort of over-the-counter pills you just take and there's nothing needs to be managed. You're describing something where actually like there's quite a lot of management that needs to happen in the first few months with lots of different results, despite the way that it's working so well and that you're saying the side effects are relatively low. This is something that really needs to be quite carefully taken on because it's really going to change the way that you feel. Absolutely. I fear a little bit that as

some of the primary care providers start taking this on, which I strongly encourage them to do so because there's many patients who would benefit from this kind of treatment, is that they have the awareness, familiarity, knowledge, and bandwidth in their practice to actually manage patients carefully. I am concerned about the internet distribution and use of this medication because it's the opposite of what we're talking about on this podcast, right? That is just take the shot and go on your way and get thin. That is the wrong message. So for the listeners, there were a series of step trials. There have been multiple clinical trials using this drug at this point. And I think it's important for people to understand that for every

single one of these trials, diet and lifestyle was a part of what was done. And this should be a part of how we support our patients when they transition to these drugs, that we shouldn't exclude diet and lifestyle, that these are not mutually exclusive choices. Let me add something to that, Will. As someone who runs a center for lifestyle medicine at my institution, I've had the opportunity to work in individuals who have struggled with their weight for years, if not decades, because as we talked before about the weight regain, biological adaptation, they know nutrition because we've talked about it repeatedly, but they struggle following or adhering to the diet and lifestyle recommendations we've talked

about. When we use now a medication like semaglutide for the first time in their life, and I hear this all the time, I'm not struggling. I'm not hungry. I don't feel this compulsivity to eat. I'm content. I'm not thinking of food all the time. And now they're actually able to follow the healthier diet that we've been talking about for years. And that's where the fun actually begins, Will, where we could really talk about the nuances, reducing ultra-processed foods, using foods that will increase satiety naturally, like higher protein-based foods, more plant-based diets, getting in more physical activity, doing resistance training. So for many of these individuals, it opens up the opportunity to adhere to and start to explore a lot of the lifestyle

recommendations we've talked about for years, but they've been unable to actually do it successfully. That makes complete sense. Bob, we were talking a moment about the side effects associated with this drug, and we've talked mostly about the GI side effects. But one of the things that really comes up on social media and people are concerned about is the connection between this drug and risks of cancer. So could you kind of comment on that, unpack that for us so that we understand that better? In the preclinical trials, in other words, the animal studies, there was one cancer which was identified, which is called

medullary thyroid carcinoma in certain animals. That has to do with, in part, the way this drug works, the cells that it activates. That has really not been seen in humans, although there's a warning that any individual with a history of medullary thyroid carcinoma in their family should not take this drug. So that's really the only cancer that really came up as a concern. Another concern that came up earlier is pancreatitis, not a cancer, but I'm thinking in form of side effects. That still has a warning when you use the drug, although that hasn't been seen in any of the STEP trials. So that's the concern regarding that. Whether it actually reduces the occurrence of cancer in some individuals,

I think it's yet to be seen. We don't really know about that. But I can tell you my cancer colleagues or oncology specialists are very intrigued by this medication because obesity itself is a risk factor for many types of cancers, breast cancer, gallbladder cancer, uterine cancer. So they see this as a potential adjunctive treatment to reduce the occurrence of cancer or the reoccurrence of cancer in a woman, let's say who's's post-breast cancer as another long-term treatment.

Yeah, I think it's very exciting to see where it goes because so many different forms of cancer are tied to obesity. With regard to the thyroid cancer, real quick, there is a genetic condition, multiple endocrine neoplasia type 2, MEN type 2, which is a contraindication to using the drug because that condition is associated with this type of thyroid cancer. But Bob, if a person is in your clinic and says, I have a family member who had thyroid cancer, how would you approach that? Is a family risk something that would stop you? So I'm glad you brought up MEN 2 along with medullary thyroid carcinoma. Those are the absolute contraindications.

There is no connection that we are aware of the thyroid cancer that someone's more likely to have follicular thyroid cancer. We don't see that as a connection, so that would not be a contraindication. If I see someone in a clinic and take a family history of thyroid cancer, I try to clarify what kind of thyroid cancer, I try to clarify what kind of thyroid cancer that is. So that is not a contraindication. But if it was a medullary thyroid cancer, would you have a concern?

Yes, I would. I would not give it to someone with a history or family history of medullary thyroid carcinoma. Bob, I'd love to take the chance to maybe come to this question that I think is going to be on a lot of listeners' minds, which is, you know, maybe I don't have obesity, but I know that I'm overweight. I've tried all of these different ways to lose the weight and I haven't been able to do so. This sounds amazing and it's having a lot of, you know, my weight is having a lot of effect on my life. What's the right message for those listeners today? Two messages.

One is probably worth mentioning. What is the actual indication to prescribe this medication? Let me start there. And it's based on something called body mass index or BMI, which I think is an awful way of describing a disease, which is a height weight relationship body size but it is indicated for an individual with a BMI of 30 or more or 27 or more with a medical complication like diabetes high blood pressure high fats but that deck gets you in the door for the prescription if you don't meet that then

you'd be prescribed would be using it off-label or you don't have that indication. If someone has an increased body mass index and no medical problems whatsoever, I have a long discussion with them. First, I double down on lifestyle, eating a healthy diet, balanced diet, calorie deficit, reducing ultra-processed foods, more plant-based is the way that I think about it, robust physical activity, good sleep hygiene, don't use substances like alcohol, tobacco, and social environment. I really talk a lot about that. They're already following that and they still have an excess body weight or body fat. And medication is potentially indicated by the BMI.

I will make it very clear to them that medication works only as long as you take it. So I talk to them and I say, are you prepared to use a medication long-term, even though you just want to lose 20 pounds or 10 kilograms, are you prepared to use this medication long-term? Because we don't think of it as a jumpstart. Many people come in, I just need a jumpstart doc. This is not a jumpstart. This is a medication used long-term for a chronic relapsing condition called obesity. So I make sure they understand that. I still may end up using the medication, but I'm always touching base with them about why are we using

it? What are your expectations? What are your goals? That thing about the stopping is something that I really want to follow up on because everything about this is so magical. It is extraordinary you can lose this weight. There's definitely the sting in the tail, right? Ideally, you would take this and it would treat your problem, right? That's always great. But this feels like classic for a sort of pharmaceutical drug. like you have to keep taking it. And if you stop taking it, it stops working. Could you tell us a bit more about what happens? Because I think, you know, a lot of people are probably thinking about this, like, I get to take it for a bit, and it's going to solve my weight problem. And then I'm not going to take it anymore.

What happens if you stop? It's important to frame the conversation of what obesity is before I get into what happens when you stop it. And I used to compare it all the time of either hypertension, asthma, or diabetes. And that is these are chronic medical problems that you take a medication for. And if you stop taking the medication, those medical problems are likely to come back, whether it's diabetes, asthma, hypertension. I think people understand that. So if you go on a statin agent for high cholesterol, most people say, okay, I get it. I need to use it long-term to keep my LDL cholesterol down. So I frame it in the same context. Obesity is like a chronic disease like that. If you stop taking the

medication, there's a high likelihood the obesity is going to come back. So how does it come back? It comes back primarily, and it's very subtle. People will say, I'm starting to eat a little more food because I'm not as content as I was when I took the medication. I'm starting to snack a little bit more or nibble throughout the day, which I wasn't doing for a long period of time. I'm starting to have enjoyment of foods, an enticement of foods that I didn't have before. Very, very subtle, but that's how the medication works it alters your perception of how much food you need and that's what keeps you in a calorie deficit to lose weight in a lower calorie intake thereafter so it's very subtle and when I see patients

come back either they ran out of medication or they or they confined it in the pharmacy and they'll come back two weeks to a month later and say I've already gained a few kilograms or a few later and say, I've already gained a few kilograms or a few pounds and I explore them what's going on. And that's what they tell me. I'm just starting to eat a little bit more food. So that's how the drug works, changes your sense of appetite. Yeah, Bob, a quick comment first. So we mentioned earlier the indications for this drug and the indications that you mentioned of body mass index of 30 or 27 and above with a comorbidity. Those are the FDA

approvals in the United States. But just for the UK listeners, approval in the UK is slightly different. So as this drug reaches approval in different countries, each of the individual countries may have slight differences in how they're actually bringing it to market. With As this drug reaches approval in different countries, each of the individual countries may have slight differences in how they're actually bringing it to market. With regard to what you were just talking about, Bob, you actually just published a paper on this specific topic, which is the weight regain after discontinuing the drug. You published it in October of 2022. And I found it to be very interesting.

There was one particular graph in the paper where you could literally see the weight coming back. And it appears to me that eventually everyone gets back to almost the same baseline. So it's almost like the baseline that was established before you started the drug is where your body thinks you're supposed to be. Do you have any thoughts on that? Yeah. Well, what you're the drug is where your body thinks you're supposed to be. Do you have any thoughts on that? Yeah. Well, what you're referring to is a step one extension trial. And just to bring all listeners up to speed, we took about 300 individuals who were in that step trial that we described before, that 68-week trial, and followed them for

a year. No intervention, just follow them as if they stopped taking it. And what we found, Will, at the end of one year is that individuals on average regained two-thirds of the weight that they lost over that first year. And if we follow them long enough, they would probably get back to baseline, which is what you're saying. So that speaks to this whole idea that there's a biological set point. That's a new term we're introducing today in the podcast. A set point that the brain has of where you ought to be.

That gets back to that whole famine and starvation concept I talked about before. So the body doesn't forget. It's under the category of unfair. But the body, the brain doesn't quite forget where you started. And it works its way very slowly over the course of one to probably five years to get you back to where you were. Now, you can introduce a change in your diet again, reduce calories, increase physical activity, drive the body weight down again. But again, over time, it's likely to go up. We see this in animal studies all the time. We change the rat child.

We change how many times, you know, how often they're on the treadmill and the rats go back to the weight that they started at. And we are a biological being and our bodies behave in a very similar way. There's only two interventions that I am aware of that change this set point of where the brain thinks you ought to be. One is medications. We're talking about that today. The other is bariatric surgery. Yeah, that's interesting. And bariatric surgery is a part of this conversation too. There's going to be some people who these medications don't actually achieve the fact that we're looking for, or they, or we may achieve, you know, 15% weight loss, but we want more

than that. I think bariatric surgery is a model that we understand with much more clarity because we have more experience with it. There is a problem in bariatric surgery with weight regain that takes place. Now, one of the ways that you can prevent weight regain is with a high quality diet, such as a Mediterranean diet. With these drugs, Bob, is it too early for us to tell if weight regain is a possibility in the future? We don't have that answer right now. I can tell you definitively that at least two years of the medication, which was actually one of the STEP trials, individuals maintain that weight loss as long as they're on the medication out to two years. That's the longest data we have. Now, we have other data from individuals with

type 2 diabetes who have been using these drugs much longer, although weight loss was not the primary outcome. It's more diabetes control and they tend to maintain a lower body weight as well but it's not as clear whether it's the same weight we don't have that information i would hypothesize that weight will be maintained lower than when you started but whether it'll be maintained the exact weight uh you've reached you achieved after one or two years i don't know i think it's fascinating. So firstly, there is this like, it is a magic bullet. It's extraordinary compared to anything I think we've seen before. And yet it does have this sort of sting in the tail, right? Which is that you have to keep taking

it. I guess the other thing that I'm really struck by having been in a lot of these podcasts, I think many listeners have, where a lot of the story that comes up from a lot of different scientists in their research is that there seems to be something profoundly wrong in our current environment. Compared to 100 years ago, almost nobody would get obesity. And you're telling us this story that I think in another 12 years, 50% of all Americans will have obesity. And so that's clearly part of the food that we eat, the environment we're in, what may be happening to our microbiome, all of these sorts of things. And so then the pharmaceutical industry does come up with what is clearly a wonder drug, right? And I think, you know, Bob, it's really clear, you're very, very excited about it. And you can see that it can have a profound impact on a lot

of people's lives, which is wonderful. And I guess what I feel is if we were talking about cancer, we would be talking about treatment for cancer and all the great drugs to treat cancer. But we would also be spending a lot of time talking about the causes of cancer. And in fact, we put a great deal of effort, right, to remove all sorts of things in our environment that might cause it. Is there a danger that we sort of say, hey, problem solved, we've got this drug, you know, in a few years time, everybody will start taking this when they're, you know, 18 for the rest of their life. And we sort of forget about the other half. I don't think that will occur. I mentioned earlier that we think of obesity, I think of as a two prong problem. First and foremost, it's a public health problem that is not spread globally.

We're never going to have a medication approach to a public health problem like that. It's too deep-rooted, as you said, in our environment, our food supply regulation, how we live our life, the air, obesogens, plastics, and all these types of things we're learning more and more. It's going to need multiple stakeholders. I kind of look at that as like a moonshot. We need to put everyone in a room, block the room until we come up with some solution, and then give it a trial and see how that works. I don't ever think of it that way. The way I think about medication is when I see an individual come into my office who is suffering from obesity, sleep apnea, type 2 diabetes, fatty liver disease, arthritis where their knees hurt, urinary incontinence,

it goes on to 200 medical problems. What do I have to offer that individual who's coming in with me today with a high risk morbidity, mortality, reduced quality of life? I have something to offer that individual. But by no way do I think I am solving the public health problem of obesity. We need to deal with those both together and at the same time. Amazing. So Bob, maybe to conclude, if some of our listeners are worried about their weight and they feel that based on today's conversation, these drugs could be relevant for them, what would be the next step? Make an appointment with your healthcare professional. Be prepared to ask very targeted and specific questions. How can you help me? Are there

medications that can assist me in losing weight and improving my health? Have you heard of these new GLP-1 receptor agonists? Somaglotype would be an example, or there's others. What other resources or referrals do you have for me so I could be more successful taking control of my own life? And lastly, if you don't have answers to that, who can you refer me to that can provide that support? Brilliant, Bob. Well, this has been fascinating. One of the things we always do at the end of the podcast is I try and sum up. So I'm relying on both you and Will to keep me honest as a non-doctor in the room. So I think the first thing that I learned is that semaglutide mimics a natural hormone that's actually created in our gut that makes us full, that it really is a game changer. It's not just the media hype, but here we're talking to a doctor who's been in his field for decades, did the trial, and you're really saying, look, this is a really

big change. And that's because it's profoundly addressing this really big challenge in weight loss, which is, yes, partly how much do you lose weight immediately, but this sort of way in which your body's trying to fight back against it. And with these drugs, you're just not hungry all the time. You're not struggling all the time. And therefore, you're able, instead of losing 3%, as you gave an example on the other arm, you're losing 15% of your weight, which is obviously an enormous amount. It needs to be injected. So it's not just a pill. You are injecting, but you can self-ject it once a week. There are some side effects. And I think you said they're mainly sort of gut related, like nausea, diarrhea, but actually in many people, actually they subside. And this is part

about managing the treatment in the first few months. Now, all of that is amazing. Like it sidesteps all this human adaptation to try and react to famine by keeping on your weight. But there is one big downside, which is you don't just do this for a couple of months and stop. This is basically, at the moment, it's like you've got to do this for the rest of your life. Because if you stop, you just depressingly slowly put the weight on sort of month on month and get back to beginning. And so it's potentially amazing drugs, but it's sort of treating the symptoms of something which is going on in our society and I think the figures that you shared was you know obesity

in the US was 13% in the 1990s and will be 50% by a dozen years from now and I think the final thing you said is if anybody's listening to this and is interested then they need to go to their physician their doctor ask some really clear questions And I think I also heard a lot of concern about people who might be trying to do this sort of over the internet in a way that is not well managed. Well said. I think you did a wonderful summary. Well, Bob and Will, thank you so much for spending the time. Bob, I'm sure that the phone has been ringing off the hook over the last few months on this topic. So really appreciate it. And it's wonderful to really understand, I think, some of the facts. Thank you for having me. It's enjoyable.

We'll be able to have you back again in the future because it sounds like this is still relatively early, right? So over the next year or two, we're starting to have a lot more data about sort of longer term follow up. And I think, as Will also mentioned, like there's an enormous amount of sort of pharma industry in this area, isn't there? So there are like even more potentially even better drugs that are going to come in the next few years. This is the beginning of a whole range of emerging compounds that are mixing and matching multiple gut hormones with the likelihood of even more

effective treatments around the horizon. I love it. Well, the power of the gut, we like to talk about that. So it's very exciting. Thank you so much. Thank you. Thank you, Bob and Will, for joining me on Zoe's Science and Nutrition today. I think it's clear this is a pretty amazing breakthrough in understanding the science of weight management with huge potential for many people living with obesity and I'm excited to see what the future holds. If based on today's conversation you're interested in improving your own health and perhaps achieving a healthy weight without drugs then you may want to try Zoe's

personalized nutrition program so you can feel more energetic, improve your gut health and reduce the risk of long-term disease. Your Zoe membership gives you meal and recipe recommendations and scientifically backed nutrition advice on how to eat for your best health. Your personalized nutrition program is based on our scientific research and the results of your personal at-home test. If you're interested in learning more about Zoe, you can head to joinzoe.com slash podcast and get 10% off your purchase. As always, I'm your host, Jonathan Wolfe. Zoe Science and Nutrition is produced by Fascinate Productions

with support from Sharon Fedder, Yellow Hewings Martin, and Alex Jones here at Zoe. See you next time.